The aspartate-257 of presenilin 1 is indispensable for mouse development and production of β-amyloid peptides through β-catenin-independent mechanisms

Xuefeng Xia, Pei Wang, Xiaoyan Sun, Salvador Soriano, Wan Kyng Shum, Haruyasu Yamaguchi, Myrna E. Trumbauer, Akihiko Takashima, Edward H. Koo, Hui Zheng

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

To differentiate multiple activities of presenilin 1 (PS1), we generated transgenic mice expressing two human PS1 alleles: one with the aspartate to alanine mutation at residue 257 (hPS1D257A) that impairs the proteolytic activity of PS1, and the other deleting amino acids 340-371 of the hydrophilic loop sequence (hPS1Δcat) essential for β-catenin interaction. We show here that although hPS1Δcat is fully competent in rescuing the PS1-null lethal phenotype, hPS1D257A does not exhibit developmental activity. hPS1D257A also leads to the concurrent loss of the proteolytic processing of Notch and β-amyloid precursor protein (APP) and the generation of β-amyloid peptides (Aβ). Further, by measuring the levels of endogenous AβX-40 and AβX-42 in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Aβ.

Original languageEnglish (US)
Pages (from-to)8760-8765
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number13
DOIs
StatePublished - Jun 25 2002
Externally publishedYes

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